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  • Title: The effect of diethyldithiocarbamate on the biodisposition of MPTP: an explanation for enhanced neurotoxicity.
    Author: Irwin I, Wu EY, DeLanney LE, Trevor A, Langston JW.
    Journal: Eur J Pharmacol; 1987 Sep 11; 141(2):209-17. PubMed ID: 2824216.
    Abstract:
    Diethyldithiocarbamate (DDC) has been reported to exacerbate the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. In this study, the effects of DDC on the biotransformation and distribution of MPTP and 1-methyl-4-phenylpyridinium ion (MPP+, the putative toxic metabolite of MPTP) were investigated. When DDC was administered prior to a standardized dosage of MPTP, the initial concentrations of MPTP in striatum, ventral mesencephalon and frontal cortex were markedly increased when compared to animals given MPTP alone. The pre-administration of DDC also produced increased concentrations of MPP+ in these regions at all time points studied. Further, the rate of disappearance of MPP+ from brain was significantly less in DDC pretreated animals, when compared to animals given MPTP alone. In vitro studies, using either brain homogenates or partially purified MAO-B, showed that DDC enhanced the biotransformation of MPTP. These results suggest that DDC enhances MPTP-induced neurotoxicity by increasing brain concentrations of MPP+. Factors contributing to this increase appear to include greater delivery of MPTP to the central nervous system (CNS), increased biotransformation of MPTP to MPP+ via MAO, and possibly reduced clearance of MPP+ from the brain.
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